Tramadol is a widely prescribed analgesic, with 18,526,000 prescriptions and $281,559,000 in retail sales in 2007, making it the 31st best selling generic drug. One of the advantages of tramadol over traditional opioids is its lower risk of opioid dependence, resulting in it having an unscheduled status in the U.S. and other countries. Although its mode of action is not completely understood, its analgesic activity is due to synergy between both the parent drug and the desmethyltramadol (M1) metabolite. The production of M1 and its opioid activity is critically dependent on the polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Approximately 10% of Caucasians have a genotype that results in reduced activity of CYP2D6. These individuals are poor metabolizers (PM) of tramadol, and their M1 serum concentration is significantly less than normal subjects. Several well- controlled clinical trials have shown that the analgesic effect of tramadol is decreased or absent in PM subjects who have low CYP2D6 enzymatic activity. The impact of tramadol resistance in 10% of the U.S. population with low or absent CYP2D6 activity is significant, with upwards of 600,000 patients potentially receiving inadequate analgesia from tramadol therapy. Further, the need to switch non- responders to traditional opioids increases their risk of opioid dependence. Within this need-analysis, there exists an opportunity to develop an "improved tramadol" that would be effective in all patients. Such a product would be expected to be quickly adopted by the market and displace existing tramadol sales. Based on the known pharmacokinetic and efficacy data for tramadol and its M1 metabolite, we hypothesize that a combination tablet comprising tramadol and its M1 metabolite can be developed that will overcome tramadol resistance in PMs by directly supplementing these patients with the M1 metabolite that they are incapable of generating on their own. By providing both the M1 metabolite and the parent drug, the entire spectrum of opioid and monoaminergic activity will be restored in subjects with the PM phenotype. Based on the known therapeutic index of tramadol, we further hypothesize that such a combination tablet will provide safe and effective analgesia in normal subjects as well. Such a combination tablet will obviate the influence of a patient's CYP2D6 genotype on tramadol efficacy. Not having to consider if a patient who requires analgesia with tramadol has the the CYP2D6 PM genotype will be a clear prescribing advantage to physicians. PUBLIC HEALTH RELEVANCE: Pain is a leading cause of human disability effecting ~1% of the population. Tramadol is a widely prescribed pain medication that was prescribed 18,526,000 times in 2007. An important advantage of tramadol is its lower risk of opioid dependence. Approximately 10% of Caucasians can not use tramadol because they fail to process the drug appropriately. This project will develop a new, improved tramadol that can be processed by all people for their benefit.